Aqueous suspension preparations

ABSTRACT

Addition of polyvinylpyrrolidone and a water-soluble anionic macromolecular compound to an aqueous suspension of a hardly soluble drug allows to provide an aqueous suspension in which aggregation of drug particles, formation of macro crystals from suspended particles and formation of secondary particles from deposited particles are prevented, and adhesion and adsorption to containers made of plastics, e.g., polypropylene or polyethylene, are avoided. As it has a good redispersibility, the aqueous suspension is useful as eye drops, nasal drops, ear drops, injections, oral preparations, liniments and lotions.

TECHNICAL FIELD

[0001] The present invention relates to an aqueous suspension with goodredispersibility comprising polyvinylpyrrolidone and a water-solubleanionic macromolecular compound which are added to prevent a hardlysoluble drug from adhering to a container and forming aggregates.

BACKGROUND ART

[0002] Aqueous suspensions often have problems such as difficulty inredispersion due to aggregation of drug particles, formation of macrocrystals from suspended particles or formation of secondary particlesfrom deposited particles, any of which could take place during long-termstorage or when they are exposed to temporary heating or fluctuation oftemperature/humidity. In addition, some types of suspended particlesadhere to or get adsorbed by the walls of a plastic container and couldthus cause a problem of unstable concentration of the drug contained inthe aqueous suspensions.

[0003] To address these problems, measures have been taken in order toprevent formation of secondary particles by blocking sedimentation byreducing the size of the particles in suspension and increasing theviscosity of the dispersion medium with a water-soluble macromolecularcompound, or to prevent aggregation of particles in the suspension byincreasing the size of the particles in the suspension and therebyexpanding the space between deposited particles. However, while it isnot possible to completely prevent sedimentation of suspended particlesby reducing the size of the particles in the suspension and increasingthe viscosity of the dispersion medium, this measure could cause aproblem by making it more difficult to redisperse particles which areonce deposited from the suspension. On the other hand, increasing of thesize of particles in the suspension would cause problems such as foreignbody sensation upon application or clogging of a container nozzle or asyringe needle.

[0004] In this situation, it is disclosed in Japanese Patent ApplicationPublication H8-295622 that an aqueous suspension with goodredispersibility can be obtained by addition of an ionic macromolecularcompound such as carboxyvinyl polymer or carboxymethylcellulose and ametal cation such as sodium or potassium ion, and adjusting theviscosity to 100 cP. This method, however, cannot be used when highlevels of viscosity is desired for improvement of the retention of adrug, because the redispersibility in this method is acquired by its lowviscosity of 100 cP.

[0005] On the other hand, it is disclosed in EP0995435A1 (WO 98/51281)that an aqueous suspension with good redispersibility is obtained byaddition of a water-soluble macromolecular compound within aconcentration range from the concentration at which the surface tensionof the aqueous suspension begins to decrease up to the concentration atwhich the reduction in the surface tension ceases. As it employs lowconcentrations of an aqueous macromolecular compound, this method cannotbe used, either, when addition of higher concentrations of themacromolecular compound is needed for other reasons, e.g., forimprovement of the retention of a drug.

[0006] Thus, there have been needs for an aqueous suspension with goodredispersibility irrespective of its viscosity or of the amount ofsuspending and thickening agents such as water-soluble macromolecularcompounds.

DISCLOSURE OF INVENTION

[0007] The objective of the present invention is to provide an aqueoussuspension with good redispersibility.

[0008] As a result of studies performed to solve the above-mentionedproblems, the inventors of the present invention surprisingly found thataddition of polyvinylpyrrolidone and a water-soluble anionicmacromolecular compound improves the redispersibility of hardly solubledrugs in an aqueous suspension, and completed the present inventionbased on the finding.

[0009] Thus, the present invention relates:

[0010] (1) An aqueous suspension comprising a hardly soluble drug,polyvinylpyrrolidone and a water-soluble anionic macromolecularcompound,

[0011] (2) the aqueous suspension defined above in (1), wherein thelower and the upper limit concentrations of polyvinylpyrrolidone areabout 0.1 w/v % and about 10 w/v %, respectively, and the lower and theupper limit concentrations of the water-soluble anionic macromolecularcompound are about 0.05 w/v % and about 1.0 w/v %, respectively,

[0012] (3) the aqueous suspension defined above in (1), wherein theconcentration of polyvinylpyrrolidone is 0.1-5.0 w/v % and thewater-soluble anionic macromolecular compound is contained at a weightratio of 0.1-2.0 to the amount of polyvinylpyrrolidone,

[0013] (4) the aqueous suspension defined above in (2) or (3), whereinthe hardly soluble drug is at least one selected from steroidalantiinflammatory drugs, antiphlogistic-analgesics, chemotherapeutics,synthetic antimicrobials, antivirals, hormones, anti-cataract drugs,neovascularization suppressants, immunosuppressants, proteaseinhibitors, aldose reductase inhibitors, antiallergics, anxiolytics,antipsychotics, antibiotics, antitumor drugs, anti-hyperlipemic drugs,antitussive-expectorants, muscle relaxants, antiepileptics, antiulcerdrugs, antidepressants, cardiotonics, antiarrhythmic drugs,vasodilators, antihypertensive-diuretics, antidiabetics,antituberculosis drugs, narcotic antagonists, drugs for dermatologicdiseases and diagnostic drugs,

[0014] (5) the aqueous suspension defined above in (4), wherein thehardly soluble drug is a steroidal antiinflammatory drug,

[0015] (6) the aqueous suspension defined above in (5), wherein thesteroidal antiinflammatory drug is at least one selected from cortisoneacetate, hydrocortisone acetate, betamethasone, prednisolone,fluticasone propionate, dexamethasone, triamcinolone, loteprednol,fluorometholone, difluprednate, momethasone furoate, clobetasolpropionate, diflorasone diacetate, diflucortolone valerate,fluocinonide, amcinonide, halcinonide, fluocinolone acetonide,triamcinolone acetonide, flumethasone pivalate and clobetasone acetate,

[0016] (7) the aqueous suspension defined above in (4), wherein thehardly soluble drug is an anti-cataract drug,

[0017] (8) the aqueous suspension defined above in (7), wherein theanti-cataract drug is pirenoxine orN-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal,

[0018] (9) the aqueous suspension defined above in (4), wherein thehardly soluble drug is an antiphlogistic-analgesic,

[0019] (10) the aqueous suspension defined above in (9), wherein theantiphlogistic-analgesic is at least one selected from alclofenac,alminoprofen, indomethacin, epirizole, oxaprozin, ketoprofen, diclofenacsodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid,flurbiprofen, floctafenine, pentazocine, metiazinic acid, mefenamicacid, mofezolac, salicylic acid, sulpyrine, atropine, scopolamine,morphine, pethidine, levorphanol, oxymorphone and salts thereof,

[0020] (11) the aqueous suspension defined above in one of (1)-(10),wherein the water-soluble anionic macromolecular compound is at leastone selected from anionic polysaccharides, anionic polyvinyl-basedpolymers and anionic macromolecular polypeptides,

[0021] (12) the aqueous suspension defined above in (11), wherein theanionic polysaccharide is at least one selected fromcarboxymethylcellulose or a salt thereof, alginic acid or a saltthereof, chondroitin sulfate or a salt thereof, pectin and xanthan gum,

[0022] (13) an aqueous suspension comprising a steroidalantiinflammatory drug, polyvinylpyrrolidone and alginic acid or a saltthereof,

[0023] (14) the aqueous suspension defined above in (11), wherein thelower and the upper limit concentrations of polyvinylpyrrolidone areabout 0.1 w/v % and about 10 w/v %, respectively, and the lower and theupper limit concentrations of alginic acid or a salt thereof are about0.05 w/v % and about 1.0 w/v %, respectively,

[0024] (15) an aqueous suspension comprising an anti-cataract drug,polyvinylpyrrolidone and alginic acid or a salt thereof,

[0025] (16) the aqueous suspension defined above in (15), wherein thelower and the upper concentrations of polyvinylpyrrolidone are about 0.1w/v % and about 10 w/v %, respectively, and the lower and the upperlimit concentrations of alginic acid or a salt thereof are about 0.05w/v % and about 1.0 w/v %, respectively,

[0026] (17) the aqueous suspension defined above in (16), wherein theanti-cataract drug is pirenoxine,

[0027] (18) an aqueous suspension comprising anantiphlogistic-analgesic, polyvinylpyrrolidone and alginic acid or asalt thereof,

[0028] (19) the aqueous suspension defined above in (18), wherein thelower and the upper concentrations of polyvinylpyrrolidone are about 0.1w/v % and about 10 w/v %, respectively, and the lower and the upperlimit concentrations of alginic acid or a salt thereof are about 0.2 w/v% and about 1.0 w/v %, respectively,

[0029] (20) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of eye drops,

[0030] (21) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of nasal drops,

[0031] (22) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of ear drops,

[0032] (23) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of an injection,

[0033] (24) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of an oral preparation,

[0034] (25) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of a liniment,

[0035] (26) the aqueous suspension defined above in one of (1)-(19),wherein the aqueous suspension is in the form of a lotion,

[0036] (27) a method for improving the redispersibility of an aqueoussuspension of a hardly soluble drug comprising addition ofpolyvinylpyrrolidone and a water-soluble anionic macromolecular compoundto the aqueous suspension,

[0037] (28) the method defined above in (27), wherein the lower and theupper concentrations of polyvinylpyrrolidone are about 0.1 w/v % andabout 10 w/v %, respectively, and the lower and the upper limitconcentrations of the water-soluble anionic macromolecular compound areabout 0.05 w/v % and about 1.0 w/v %, respectively, and

[0038] (29) the method defined above in (27), wherein the concentrationof polyvinylpyrrolidone is 0.1-5.0 w/v % and the water-soluble anionicmacromolecular compound is contained at a weight ratio of 0.1-2.0 to theamount of polyvinylpyrrolidone.

[0039] Examples of polyvinylpyrrolidone (INN: povidon) used in thepresent invention include, e.g., polyvinylpyrrolidone K15 (K: intrinsicviscosity, i.e., Fikentscher's K-Value), polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidoneK60 and polyvinylpyrrolidone K90, among which polyvinylpyrrolidone K25and polyvinylpyrrolidone K30 are preferable.

[0040] Examples of anionic polysaccharides which are within the scope ofthe water-soluble anionic macromolecular compounds used in the presentinvention include carboxymethylcellulose and salts thereof, alginic acidand salts thereof, chondroitin sulfate and salts thereof, pectin andxanthan gum. Examples of salts of carboxymethylcellulose include sodiumsalt and calcium salt. Examples of salts of alginic acid include sodiumsalt, potassium salt, calcium salt, and sodium-calcium salt. Examples ofsalts of chondroitin sulfate include sodium salt, potassium salt andcalcium salt. Carboxymethylcellulose and salts thereof or alginic acidand salts thereof are preferred, among which sodium alginate isparticularly preferred.

[0041] Examples of anionic polyvinyl-based polymers which are within thescope of the water-soluble anionic macromolecular compounds used in thepresent invention include carboxyvinyl polymers.

[0042] Example of anionic macromolecular polypeptides which are withinthe scope of the water-soluble anionic macromolecular compounds used inthe present invention include gelatin (type B).

[0043] The concentration of polyvinylpyrrolidone may be determined asdesired between the lower limit of about 0.1 w/v %, preferably about 0.3w/v % and the upper limit of about 10 w/v %, preferably about 5 w/v %,more preferably about 2 w/v %. The concentration of a water-solubleanionic macromolecular compound may be determined as desired between thelower limit of about 0.05 w/v %, preferably about 0.1 w/v %, morepreferably about 0.2 w/v % and the upper limit, which is lower thanthose concentrations that trigger gel formation, specifically about 1.0w/v %, preferably about 0.5 w/v %.

[0044] As for a water-soluble anionic macromolecular compound, it ispreferably contained at a weight ratio of from about 0.01 to about 2.0to the weight of polyvinylpyrrolidone when the concentration ofpolyvinylpyrrolidone is from about 0.1 to about 10 w/v %, and morepreferably at a weight ratio of 0.1-2.0 to the weight ofpolyvinylpyrrolidone when the concentration of polyvinylpyrrolidone is0.1-5.0 w/v %.

[0045] Examples of hardly soluble drugs used in the present inventionmay be those which exhibit solubility as defined by any of the terms,“sparingly soluble”, “slightly soluble”, “very slightly soluble” and“practically insoluble” set forth in the Japanese Pharmacopoeia, and anydrugs are included which could be provided as aqueous suspensions intheir final forms.

[0046] Examples of hardly soluble drugs used in the present inventioninclude steroidal antiinflammatory drugs, antiphlogistic-analgesics,chemotherapeutics, synthetic antimicrobials, antivirals, hormones,anti-cataract drugs, neovascularization suppressants,immunosuppressants, protease inhibitors, aldose reductase inhibitors,antiallergics, anxiolytics, antipsychotics, antibiotics, antitumordrugs, anti-hyperlipemic drugs, antitussive-expectorants, musclerelaxants, antiepileptics, antiulcer drugs, antidepressants,cardiotonics, antiarrhythmic drugs, vasodilators,antihypertensive-diuretics, antidiabetics, antituberculosis drugs,narcotic antagonists, drugs for dermatologic diseases and diagnosticdrugs, among which steroidal antiinflammatory drugs,antiphlogistic-analgesics and anti-cataract drugs are preferred.Examples of steroidal antiinflammatory drugs include cortisone acetate,hydrocortisone acetate, betamethasone, prednisolone, fluticasonepropionate, dexamethasone, triamcinolone, loteprednol, fluorometholone,difluprednate, momethasone furoate, clobetasol propionate, diflorasonediacetate, diflucortolone valerate, fluocinonide, amcinonide,halcinonide, fluocinolone acetonide, triamcinolone acetonide,flumethasone pivalate and clobetasone acetate, among whichfluorometholone is preferred. Examples of antiphlogistic-analgesicsinclude alclofenac, alminoprofen, indomethacin, epirizole, oxaprozin,ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam,fenbufen, flufenamic acid, flurbiprofen, floctafenine, pentazocine,metiazinic acid, mefenamic acid, mofezolac, salicylic acid, sulpyrine,atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone andsalts thereof, among which indomethacin is preferred. Examples ofchemotherapeutics include sulfonamide antimicrobials such assalazosulfapyridine, sulfadimethoxine, sulfamethizole, sulfamethoxazole,sulfamethopyrazine and sulfamonomethoxine; synthetic antimicrobials suchas enoxacin, ofloxacin, cinoxacin, sparfloxacin, thiamphenicol,nalidixic acid, tosufloxacin tosilate, norfloxacin, pipemidic acidtrihydrate, piromidic acid, fleroxacin, revofloxacin; antivirals such asacyclovir, ganciclovir, didanosine, zidovudine, nevirapine, vidarabine,nelfinavir mesilate and ritonavir; antifungal agents such asitraconazole, ketoconazole, fluconazole, flucytosine, miconazole andpimaricin. Examples of hormones include insulin zinc, testosteronepropionate, estradiol benzoate, methimazole and estriol. Examples ofanti-cataract drugs include pirenoxine andN-(4-fluorophenylsulfonyl)-L--valyl-L-leucinal. Examples ofneovascularization suppressants include fumagillin and derivativesthereof. Examples of immunosuppressants include cyclosporine, rapamycinand taclorimus. Examples of protease inhibitors include[L-3-trans-ethoxycarbonyloxysilane-2-carbonyl]-L-leucine(3-methylbutyl)-amide(E-64-d). Examples of aldose reductase inhibitors include5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione. Examples ofantiallergics include tranilast, clemastine fumarate, mequitazine,diphenhydramine, chlorpheniramine, tripelennamine, methdilazine,clemizole, diphenylpyraline and methoxyphenamine. Examples ofanxiolytics include diazepam, lorazepam and oxazepam. Examples ofantipsychotics include chlorpromazine, prochlorperazine andtrifluperazine. Examples of antibiotics include gentamicin, dibekacin,kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin,tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine,cefotiam, cefotiam hexetil, cefsulodin, cefinenoxime, cefinetazole,cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam,thienamycin, sulfazecin, azthreonam and salts thereof. Examples ofantitumor drugs include 6-O-(N-chloroacetylcarbamoyl)fumagilol,bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin,adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil,tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole,bestatin, azimexon and glycyrrhizin. Examples of anti-hyperlipemic drugsinclude clofibrate and2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionic acid ethylester [Chemical And Pharmaceutical Bulletin (Chem. Pharm. Bull.), 38,2792-2796 (1990)]. Examples of antitussive-expectorants includeephedrine, methylephedrine, noscapine, codeine, dihydrocodeine,alloclamide, chlorphedianol, picoperidamine, chloperastine, protokylol,isoproterenol, salbutamol, terbutaline, and salts thereof. Examples ofmuscle relaxants include pridinol, tubocurarine and pancuronium.Examples of antiepileptics include phenitoin, ethosuccimide,acetazolamide and chlordiazepoxide. Examples of antiulcer drugs includesynthetic aluminum silicate, aldioxa, lansoprazole and metoclopramide.Examples of antidepressants include imipramine, clomipramine,noxiptyline and phenelzine. Examples of cardiotonics includetrans-n-oxocamphor, terephylol, aminophylline and etilefrine. Examplesof antiarrhythmic drugs include propranolol, alprenolol, bufetolol andoxprenolol. Examples of vasodilators include oxyephedrine, diltiazem,tolazoline, hexobendine and bamethane. Examples ofantihypertensive-diuretics include hexamethonium bromide, pentolinium,mecamylamine, ecarazine, clonidine, diltiazem and nifedipine. Examplesof antidiabetics include glymidine, glipzide, fenformine, buformin andmetformine. Examples of antituberculosis drugs include isoniazid,ethambutol, para-aminosalicylic acid. Examples of narcotic antagonistsinclude levallorphan, nalorphine, naloxone and salts thereof. Examplesof drugs for dermatologic diseases include calamine and sulfur. Examplesof diagnostic drugs include barium sulfate.

[0047] The concentrations of a hardly soluble drug in the presentinvention may be determined depending on the drug employed, the intendedpurpose and the way of application. For example, fluorometholone, asteroidal antiinflammatory drug, may be prepared at a concentration offrom about 0.02 to about 0.1 w/v % when used in the form ofsuspension-type eye drops for allergic conjunctivitis. Indomethacin, anantiphlogistic-analgesic, may be prepared at a concentration of fromabout 0.1 to about 1.0 w/v % when used in the form of suspension-typeeye drops for postoperative inflammation. Pirenoxine, an anti-cataractdrug, may be prepared at a concentration of from about 0.001 to about0.01 w/v % when used in the form of suspension-type eye drops for theincipient stage of senile cataract. Eye drops may be applied 3-5 times aday, 1-2 drops at a time. As to betamethasone, a steroidalantiinflammatory drug, when it is intravenously injected in the form ofa suspension-type injection for rheumatic fever, it maybe prepared at aconcentration of from about 0.4 to about 2.0 w/v % and administered inan amount of about 2-8 mg at a time and at intervals of 3-6 hours. Whenit is used in the form of a suspension-type oral preparation forrheumatoid arthritis, it may be prepared at a concentration of fromabout 0.01 to about 0.05 w/v % and administered 1-4 times a day, with adaily dose being from about 0.5 to about 8 mg. Also, when it is used inthe form of a suspension-type lotion for allergic eczema, it may beprepared at a concentration of from about 0.06 to about 0.12 w/v % andapplied from one to several times a day.

[0048] As to the relation between a hardly soluble drug and theconcentrations of polyvinylpyrrolidone and a water-soluble anionicmacromolecular compound in the aqueous suspension of the presentinvention, polyvinylpyrrolidone and a water-soluble anionicmacromolecular compound may be used as desired within the concentrationranges described hereinbefore, regardless of which hardly soluble drugis selected. Their particularly preferable concentration ranges whenused with a steroidal antiinflammatory drug, for example, are defined bythe lower and the upper limit concentrations of about 0.1 w/v % andabout 10 w/v %, respectively, for polyvinylpyrrolidone and by the lowerand the upper limit concentrations of about 0.05 w/v % and about 1.0 w/v%, respectively, for alginic acid or salts thereof. When used with ananti-cataract drug, such ranges are defined by the lower and the upperlimit concentrations of about 0.1 w/v % and about 10 w/v %,respectively, for polyvinylpyrrolidone and by the lower and the upperlimit concentrations of about 0.05 w/v % and about 1.0 w/v %,respectively, for alginic acid or salts thereof. When used with anantiphlogistic-analgesic, it is preferable that the lower and the upperlimit concentrations of polyvinylpyrrolidone are about 0.1 w/v % andabout 10 w/v %, respectively, and that the lower and the upper limitconcentrations of alginic acid or salts thereof are about 0.2 w/v % andabout 1.0 w/v %, respectively.

[0049] In addition to a hardly soluble drug, polyvinylpyrrolidone and awater-soluble anionic macromolecular compound, the aqueous suspension ofthe present invention may further contain, as desired, for example,isotonizers (sodium chloride, potassium chloride, glycerol, mannitol,sorbitol, boric acid, borax, glucose, propylene glycol, etc.), buffers(phosphate buffer, acetate buffer, borate buffer, carbonate buffer,citrate buffer, tris buffer, glutamic acid, ε-aminocaproic acid, sodiumacetate, boric acid, borax, etc.), preservatives (chlorobutanol, benzylalcohol, sodium dehydroacetate, sodium edetate, benzalkonium chloride,benzethonium chloride, methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, propyl p-hydroxybenzoate, boric acid, borax, etc.),thickening agents (hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylalcohol, polyethylene glycol,etc.) surfactants (polysorbate 80, polyoxyethylenehydrogenated castoroil, tyloxapol, polyethylene glycol monostearate, sucrose fatty acidester, etc.), stabilizers (sodium hydrogen sulfite, sodium thiosulfate,sodium edetate, sodium citrate, sodium acetate, ascorbic acid,dibutylhydroxytoluene, boric acid, borax, etc.), topical astringents(zinc oxide, bismuth subgallate, etc.), topicalantiphlogistic-analgesics (d-camphor, dl-camphor, dl-menthol, etc.),dispersion stabilizers (bentonite, tragacanth, gum arabic, gelatin,etc.), pH adjusting agents (hydrochloric acid, sodium hydroxide,phosphoric acid, acetic acid, etc.), flavoring agents (simple syrup,lactose, glucose, honey, bitter tincture, etc.), sweetening agents(fructose, xylitol, sorbitol, simple syrup, lactose, etc.) and aromaticsubstances (orange oil, spearmint oil, lemon oil, rose oil, menthol,peppermint oil, etc.).

[0050] Though the amount of these additives may be determined dependingon which additives are chosen, and on their intended use, they may beadded at concentrations that allows to accomplish the purpose of theiraddition. Thus, for example, an isotonizer may usually be added at aconcentration of from about 0.5 to about 5.0 w/v % to give an osmoticpressures of from about 229 to about 343 mOs/Kg.H₂O. Likewise, a buffermay generally be added at a concentration of from about 0.01 to about2.0 w/v %, and a thickening agent, from about 0.01 to about 1.0 w/v %, asurfactant, from about 0.01 to about 10.0 w/v %, and a stabilizer, fromabout 0.001 to about 1.0 w/v %. A pH adjusting agent may be added asdesired to adjust the pH to a value of from about 3 to about 9,preferably from about 4 to about 8.

[0051] The excellent redispersibility of the aqueous suspension of thepresent invention allows itself to be used as a medicament (e.g., drugsfor prophylaxis or treatment of various diseases) for a human and as aveterinary drug for other mammalian animals (e.g., rats, mice, guineapigs, monkeys, dogs, bovines, pigs, etc.).

[0052] The aqueous suspension of the present invention may be used inthe forms of eye drops, nasal drops, ear drops, an injection, an oralliquid preparation, a liniment and a lotion, among which eye drops areespecially preferred.

BEST MODE FOR CARRYING OUT THE INVENTION

[0053] The present invention is described in further detail below withreference to the test examples and the working examples.

TEST EXAMPLE 1 Redispersibility Test

[0054] (Test Methods)

[0055] 0.1 w/v % fluorometholone suspensions containingpolyvinylpyrrolidone K25 and sodium alginate at different concentrationswere filled in polypropylene and polyethylene containers, kept at about60° C. for about 18 hours, and their appearance and redispersibilitythen were examined.

[0056] (Test Results)

[0057] The results are shown in Table 1. TABLE 1 Results ofredispersibility test of fluorometholone suspensions Sodium alginate(w/v %) 0 0.1 0.3 0.5 PP PE PP PE PP PE PP PE PVP 0.1 X X — — — — — —(w/v %) 0.3 X X ◯ ⊚ ◯ ⊚ ◯ ⊚ 0.5 X X ◯ ⊚ ◯ ⊚ ◯ ⊚ 1.0 X X ◯ ⊚ ◯ ⊚ ◯ ⊚

[0058] PVP: polyvinylpyrrolidone K25

[0059] PP: polypropylene containers

[0060] PE: polyethylene containers

[0061] In the table, X indicates that particles of fluorometholoneadhered to the container and they did not redisperse even after beingsubjected to rotation of more than 100 rounds at 40 rpm on a variablemix rotor VMR-5 (mfd. by IUCHISEIEIDO).

[0062] In the table, ◯ indicates that the particles of fluorometholonesettled down but redispersed after being subjected to rotation of 25-40rounds at 40 rpm on a variable mix rotor VMR-5 (mfd. by IUCHISEIEIDO).

[0063] In the table, ⊚ indicates that the particles of fluorometholonesettled down but redispersed simply by inverting the container.

[0064] In the fluorometholone suspensions to which was addedpolyvinylpyrrolidone alone, aggregation occurred and the particles,which adhered to the container, did not redisperse. In thefluorometholone suspension to which were added polyvinylpyrrolidone andsodium alginate, the particles showed no adhesion to the container andredispersed.

TEST EXAMPLE 2 Redispersibility Test

[0065] (Test Methods)

[0066] 0.1 w/v % fluorometholone suspensions containingpolyvinylpyrrolidone K25 and sodium alginate at different concentrationswere filled in polypropylene containers. After storage for about 18hours at about 60° C., the containers were repeatedly inverted and thenumber of times of the inversion was counted until the suspendedparticles redispersed and became non-adhesive to the container.

[0067] (Test Results)

[0068] The results are shown in Table 2. Good redispersion offluorometholone was observed with 0.1 w/v % or more polyvinylpyrrolidone(K25) and 0.05 w/v % or more sodium alginate. In contrast, in thepreparations containing 0.2 w/v % sodium alginate but nopolyvinylpyrrolidone (K25), fluorometholone floated on the surface ofthe aqueous solution and no homogeneous suspension was obtained. Thefloating fluorometholone aggregated with the lapse of time.

[0069] Test examples 1 and 2 revealed that at least certainconcentrations of polyvinylpyrrolidone and sodium alginate are bothessential for the present invention. TABLE 2 Results of redispersibilitytest of fluorometholone suspensions Sodium alginate (w/v %) 0.01 0.030.05 0.075 0.1 0.2 PVP 0 — — — — — X (w/v %) 0.1 — — — — ◯(10 times) —1.0 X X ◯(thrice) ◯(twice) — — 2.0 — — — — ◯(once) — 5.0 — — — — ◯(once)— 10.0 — — — — ◯(once) —

[0070] In the table, X indicates that the particles of fluorometholoneadhered to the container and did not redisperse.

[0071] In the table, ◯ indicates that the particles of fluorometholoneredispersed after inversion repeated the number of times indicated inthe parentheses.

TEST EXAMPLE 3 Redispersibility Test

[0072] (Test Methods)

[0073] To a 0.005 w/v % of pirenoxine suspension containing 1.0 w/v % ofpolyvinylpyrrolidone K30 was added sodium alginate at differentconcentrations, and the mixtures were filled in polypropylene andpolyethylene containers. After storage for about 18 hours at about 60°C., the containers were repeatedly inverted and the number of times ofthe inversion was counted until the suspended particles redispersed andbecame non-adhesive to the container.

[0074] The formulae of the pirenoxine suspension are shown in Table 3.TABLE 3 Formulae of pirenoxine suspensions Formula Nos. P-0 P-1 P-5Pirenoxine 0.005 g 0.005 g 0.005 g Polyvinylpyrrolidone K30 1.0 g 1.0 g1.0 g Sodium alginate — 0.1 g 0.1 g Hydrochloric acid q.s. q.s. q.s.Sodium hydroxide q.s. q.s. q.s. Purified water q.s. q.s. q.s. Totalamount 100 mL 100 mL 100 mL pH 4.0 4.0 4.0

[0075] (Test Results)

[0076] The results are shown in Table 4. TABLE 4 Results ofredispersibility test of pirenoxine suspensions Formula Nos. P-0 P-1 P-5Polypropylene containers x ∘ ∘ (thrice) (once) Polyethylene containers x∘ ∘ (twice) (once)

[0077] In the table, X indicates that the particles of pirenoxineadhered to the containers and did not redisperse.

[0078] In the table, ◯ indicates that the particles of pirenoxineredispersed after inversion repeated the number of times indicated inthe parentheses.

[0079] In the pirenoxine suspension to which polyvinylpyrrolidone (K30)alone was added, aggregation occurred in either containers, and theparticles did not redisperse and remained adhering to the containers. Inthe pirenoxine suspension to which polyvinylpyrrolidone (K30) and sodiumalginate were added, particles did not adhere to the container andredispersed after a few times of inversion.

TEST EXAMPLE 4 Redispersibility Test

[0080] (Test Method)

[0081] To a 0.5 w/v % of indomethacin suspension containing 1.0 w/v % ofpolyvinylpyrrolidone K30 was added sodium alginate at differentconcentrations, and the mixtures were filled in polypropylene andpolyethylene containers. After storage for about 18 hours at about 60°C., the containers were repeatedly inverted and the number of times ofthe inversion was counted until the suspended particles redispersed andbecame non-adhesive to the container.

[0082] The formulae of the indomethacin suspensions are shown in Table5. TABLE 5 Formulae of indomethacin suspensions Formula Nos. I-0 I-1 I-2I-3 I-4 I-5 Indomethacin 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g Sodiumacetate 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g Polyvinylpyrrolidone K30 1.0g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g Sodium alginate — 0.1 g 0.2 g 0.3 g 0.4g 0.5 g Hydrochloric acid q.s. q.s. q.s. q.s. q.s. q.s. Sodium hydroxideq.s. q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s.q.s. Total amount 100 mL 100 mL 100 mL 100 mL 100 mL 100 mL pH 5.0 5.05.0 5.0 5.0 5.0

[0083] (Test Results)

[0084] The results are shown in Table 6. TABLE 6 Results ofredispersibility test of indomethacin suspensions Formula Nos. I-0 I-1I-2 I-3 I-4 I-5 Polypropylene X Δ ◯ ◯ ◯ ◯ containers (9 (5 (5 (5 times)times) times) times) Polyethylene ◯ ◯ — — — ◯ containers (10 (thrice)(twice) times)

[0085] In the table, X indicates that the particles of indomethacinadhered to the containers and did not redisperse.

[0086] In the table, ◯ indicates that the particles of indomethacinredispersed after inversion repeated the number of times indicated inthe parentheses.

[0087] In the table, Δ indicates that the particles of indomethacinadhered to the containers in two cases in the triplicate experiment anddid not redisperse, but redispersed in one case after inversion of 12times.

[0088] The indomethacin suspensions showed container-dependency. Theirredispersibility in the polypropylene containers was improved withsodium alginate at concentrations equal to or higher than 0.2 w/v %. Inpolyethylene containers, redispersibility was improved withpolyvinylpyrrolidone (K30) alone, but further improved withpolyvinylpyrrolidone (K30) and sodium alginate.

[0089] The above results revealed that hardly soluble drugs can be madeinto suspensions with good redispersibility by addition ofpolyvinylpyrrolidone and an water-soluble anionic macromolecularcompound.

EXAMPLE 1

[0090] Eye Drops Fluorometholone 0.1 g Sodium dihydrogen phosphate,dihydrate 0.1 g Sodium chloride 0.8 g Polyvinylpyrrolidone K25 0.5 gSodium alginate 0.2 g Polysorbate 80 0.1 g Benzalkonium chloride 0.005 gSodium hydroxide q.s. Purified water to 100 mL pH 7.0

[0091] Sodium dihydrogen phosphate, dihydrate, sodium chloride,polysorbate 80, polyvinylpyrrolidone K25, sodium alginate andbenzalkonium chloride were added to about 80 mL of purified water anddissolved, and the pH was adjusted to 7 with sodium hydroxide.Fluorometholone then was added and homogeneously suspended with ahomogenizer. Addition of purified water to make the total volume of 100mL gave suspension-type eye drops containing fluorometholone.

EXAMPLE 2

[0092] Eye Drops Indomethacin 0.5 g Sodium acetate 0.1 g Sodium chloride0.8 g Polyvinylpyrrolidone K30 1.0 g Sodium alginate 0.5 g Methylp-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Hydrochloricacid q.s. Purified water to 100 mL pH 5.0

[0093] Sodium acetate, sodium chloride, polyvinylpyrrolidone K30, sodiumalginate, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate wereadded to about 80 mL of purified water and dissolved. Indomethacin thenwas added and homogeneously suspended with a homogenizer, and the pH wasadjusted to 5 with hydrochloric acid. Addition of purified water to makethe total volume of 100 mL gave suspension-type eye drops containingindomethacin.

EXAMPLE 3

[0094] Eye Drops Pirenoxine 0.005 g Sodium acetate 0.1 g Sodium chloride0.8 g Polyvinylpyrrolidone K30 1.0 g Sodium alginate 0.1 g Benzalkoniumchloride 0.005 g Hydrochloric acid q.s. Purified water to 100 mL pH 4.0

[0095] Sodium acetate, sodium chloride, polyvinylpyrrolidone K30, sodiumalginate and benzalkonium chloride were added to about 80 mL of purifiedwater and dissolved. Pirenoxine then was added and homogeneouslysuspended with a homogenizer, and the pH was adjusted to 4 withhydrochloric acid. Addition of purified water to make the total volumeof 100 mL gave suspension-type eye drops containing pirenoxine.

EXAMPLE 4

[0096] Nasal Drops Dexamethasone 0.1 g Sodium chloride 0.5 gPolyvinylpyrrolidone K25 1.0 g Sodium alginate 0.2 g Boric acid 0.7 gBorax q.s. Sodium edetate 0.0005 g Benzalkonium chloride 0.0005 g Sodiumchloride/hydrochloric acid q.s. Purified water to 100 mL pH 7.0

[0097] Sodium chloride, polyvinylpyrrolidone K25, sodium alginate, boricacid, borax, sodium edetate and benzalkonium chloride are added to about80 mL of purified water and dissolved. Dexamethasone then are added andhomogeneously suspended with a homogenizer, and the pH is adjusted to 7with sodium hydroxide/hydrochloric acid. Addition of purified water tomake the total volume of 100 mL gives suspension-type nasal dropscontaining dexamethasone.

EXAMPLE 5

[0098] Ear Drops Fradiomycin 1.0 g Boric acid 0.7 g Borax q.s. Sodiumchloride 0.5 g Polyvinylpyrrolidone K30 0.5 g Sodiumcarboxymethylcellulose 0.1 g Purified water to 100 mL pH 6.5

[0099] Boric acid, sodium chloride, polyvinylpyrrolidone K30 andcarboxymethylcellulose are added to about 80 mL of purified water anddissolved. After borax is dissolved and pH adjusted to 6.5, fradiomycinis added and homogeneously suspended with a homogenizer. Addition ofpurified water to make the total volume of 100 mL gives suspension-typeear drops containing fradiomycin.

EXAMPLE 6

[0100] Injection Betamethasone 0.8 g Polyvinylpyrrolidone K25 0.5 gSodium carboxymethylcellulose 0.5 g Polysorbate 80 0.01 g Benzalkoniumchloride 0.02 g Sodium hydroxide/hydrochloric acid q.s. Purified waterto 100 mL pH 7.0

[0101] Polyvinylpyrrolidone K25, sodium carboxymethylcellulose,polysorbate 80 and benzalkonium chloride are added to about 80 mL ofpurified water and dissolved. Betamethasone then is added andhomogeneously suspended with a homogenizer, and the pH is adjusted to 7with sodium hydroxide/hydrochloric acid. Addition of purified water tomake the total volume of 100 mL gives a suspension-type injectioncontaining betamethasone.

EXAMPLE 7

[0102] Injection Estradiol benzoate 0.1 g Polyvinylpyrrolidone K30 0.5 gSodium alginate 0.5 g Ethyl p-hydroxybenzoate 0.05 g Sodiumhydroxide/hydrochloric acid q.s. Purified water to 100 mL pH 6.5

[0103] Polyvinylpyrrolidone K30, sodium alginate and ethylp-hydroxybenzoate are added to about 80 mL of purified water anddissolved. Estradiol benzoate then is added and homogeneously suspendedwith a homogenizer, and the pH adjusted to 6.5 with sodiumhydroxide/hydrochloric acid. Addition of purified water to make thetotal volume of 100 mL gives a suspension-type injection containingestradiol benzoate.

EXAMPLE 8

[0104] Oral Suspension Synthetic aluminum silicate 5.0 g Aluminum oxide1.2 g Bitter tincture 2.0 mL Polyvinylpyrrolidone K30 1.0 g Sodiumalginate 0.2 g Simple syrup 8.0 mL Purified water to 100 mL

[0105] Glycerol, polyvinylpyrrolidone K30, sodium alginate and simplesyrup are added to about 80 mL of purified water and dissolved.Synthetic aluminum silicate, aluminum oxide and bitter tincture then areadded and homogeneously suspended with a homogenizer. Addition of waterto make the total volume of 100 mL gives an oral suspension containingsynthetic aluminum silicate.

EXAMPLE 9

[0106] Calamine lotion Calamine 8.0 g Zinc oxide 8.0 g Glycerol 2.0 mLPolyvinylpyrrolidone K30 0.5 g Carboxymethylcellulose 0.2 g Bentonite2.0 g Purified water 40.0 mL Limewater to 100 mL

[0107] Glycerol, polyvinylpyrrolidone K30 and carboxymethylcellulose areadded to 40 mL of purified water and dissolved. Calamine, zinc oxide andbentonite then are added and homogeneously suspended with a homogenizer.Addition of limewater to make the total volume of 100 mL andre-homogenization with a homogenizer gives a calamine lotion.

INDUSTRIAL APPLICABILITY

[0108] The aqueous suspension of the present invention preventsaggregation of drug particles, formation of macro crystal from suspendedparticles and formation of secondary particles from deposited particles,and blocks adhesion and adsorption to containers made of plastics suchas polypropylene or polyethylene, and provides good redispersibility. Ittherefore can be used as a good aqueous suspension in the forms of eyedrops, nasal drops, nasal drops, an injection, an oral preparation, aliniment, a lotion, etc.

[0109] The present invention is described above in detail with referenceto a limited number of specific embodiments. As it would be possible forthose skilled in the art to make various changes and modifications tothe above-described specific embodiments without substantially departingfrom the scope of the novel teachings and advantages provided by thepresent invention, the all of such changes and modifications are alsoincluded within the spirit and scope of the present invention which isdefined by the appended claims.

[0110] The present invention is based on Japanese Patent Application No.2000-255000, the entire content of which is included in the presentdescription.

1. An aqueous suspension comprising a hardly soluble drug,polyvinylpyrrolidone and a water-soluble anionic macromolecularcompound.
 2. The aqueous suspension according to claim 1, wherein thelower and the upper limit concentrations of polyvinylpyrrolidone areabout 0.1 w/v % and about 10 w/v %, respectively, and the lower and theupper limit concentrations of the water-soluble anionic macromolecularcompound are about 0.05 w/v % and about 1.0 w/v %, respectively.
 3. Theaqueous suspension according to claim 1, wherein the concentration ofpolyvinylpyrrolidone is 0.1-5.0 w/v % and the water-soluble anionicmacromolecular compound is contained at a weight ratio of 0.1-2.0 to theamount of polyvinylpyrrolidone.
 4. The aqueous suspension according toclaim 2 or 3, wherein the hardly soluble drug is at least one selectedfrom steroidal antiinflammatory drugs, antiphlogistic-analgesics,chemotherapeutics, synthetic antimicrobials, antivirals, hormones,anti-cataract drugs, neovascularization suppressants,immunosuppressants, protease inhibitors, aldose reductase inhibitors,antiallergics, anxiolytics, antipsychotics, antibiotics, antitumordrugs, anti-hyperlipemic drugs, antitussive-expectorants, musclerelaxants, antiepileptics, antiulcer drugs, antidepressants,cardiotonics, antiarrhythmic drugs, vasodilators,antihypertensive-diuretics, antidiabetics, antituberculosis drugs,narcotic antagonists, drugs for dermatologic diseases and diagnosticdrugs.
 5. The aqueous suspension according to claim 4, wherein thehardly soluble drug is a steroidal antiinflammatory drug.
 6. The aqueoussuspension according to claim 5, wherein the steroidal antiinflammatorydrug is at least one selected from cortisone acetate, hydrocortisoneacetate, betamethasone, prednisolone, fluticasone propionate,dexamethasone, triamcinolone, loteprednol, fluorometholone,difluprednate, momethasone furoate, clobetasol propionate, diflorasonediacetate, diflucortolone valerate, fluocinonide, amcinonide,halcinonide, fluocinolone acetonide, triamcinolone acetonide,flumethasone pivalate and clobetasone acetate.
 7. The aqueous suspensionaccording to claim 4, wherein the hardly soluble drug is ananti-cataract drug.
 8. The aqueous suspension according to claim 7,wherein the anti-cataract drug is pirenoxine orN-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal.
 9. The aqueous suspensionaccording to claim 4, wherein the hardly soluble drug is anantiphlogistic-analgesic.
 10. The aqueous suspension according to claim9, wherein the antiphlogistic-analgesic is at least one selected fromalclofenac, alminoprofen, indomethacin, epirizole, oxaprozin,ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam,fenbufen, flufenamic acid, flurbiprofen, floctafenine, pentazocine,metiazinic acid, mefenamic acid, mofezolac, salicylic acid, sulpyrine,atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone andsalts thereof.
 11. The aqueous suspension according to one of claims1-10, wherein the water-soluble anionic macromolecular compound is atleast one selected from anionic polysaccharides, anionic polyvinyl-basedpolymers and anionic macromolecular polypeptides.
 12. The aqueoussuspension according to claim 11, wherein the anionic polysaccharide isat least one selected from carboxymethylcellulose or a salt thereof,alginic acid or a salt thereof, chondroitin sulfate or a salt thereof,pectin and xanthan gum.
 13. An aqueous suspension comprising a steroidalantiinflammatory drug, polyvinylpyrrolidone and alginic acid or a saltthereof.
 14. The aqueous suspension according to claim 13, wherein thelower and the upper limit concentrations of polyvinylpyrrolidone areabout 0.1 w/v % and about 10 w/v %, respectively, and the lower and theupper limit concentrations of alginic acid or a salt thereof are about0.05 w/v % and about 1.0 w/v %, respectively.
 15. An aqueous suspensioncomprising an anti-cataract drug, polyvinylpyrrolidone and alginic acidor a salt thereof.
 16. The aqueous suspension according to claim 15,wherein the lower and the upper concentrations of polyvinylpyrrolidoneare about 0.1 w/v % and about 10 w/v %, respectively, and the lower andthe upper limit concentrations of alginic acid or a salt thereof areabout 0.05 w/v % and about 1.0 w/v %, respectively.
 17. The aqueoussuspension according to claim 16, wherein the anti-cataract drug ispirenoxine.
 18. An aqueous suspension comprising anantiphlogistic-analgesic, polyvinylpyrrolidone and alginic acid or asalt thereof.
 19. The aqueous suspension according to claim 18, whereinthe lower and the upper concentrations of polyvinylpyrrolidone are about0.1 w/v % and about 10 w/v %, respectively, and the lower and the upperlimit concentrations of alginic acid or a salt thereof are about 0.2 w/v% and about 1.0 w/v %, respectively.
 20. The aqueous suspensionaccording to one of claims 1-19, wherein the aqueous suspension is inthe form of eye drops.
 21. The aqueous suspension according to one ofclaims 1-19, wherein the aqueous suspension is in the form of nasaldrops.
 22. The aqueous suspension according to one of claims 1-19,wherein the aqueous suspension is in the form of ear drops.
 23. Theaqueous suspension according to one of claims 1-19, wherein the aqueoussuspension is in the form of an injection.
 24. The aqueous suspensionaccording to one of claims 1-19, wherein the aqueous suspension is inthe form of an oral preparation.
 25. The aqueous suspension according toone of claims 1-19, wherein the aqueous suspension is in the form of aliniment.
 26. The aqueous suspension according to one of claims 1-19,wherein the aqueous suspension is in the form of a lotion.
 27. A methodfor improving the redispersibility of an aqueous suspension of a hardlysoluble drug comprising addition of polyvinylpyrrolidone and awater-soluble anionic macromolecular compound to the aqueous suspension.28. The method according to claim 27, wherein the lower and the upperconcentrations of polyvinylpyrrolidone are about 0.1 w/v % and about 10w/v %, respectively, and the lower and the upper limit concentrations ofthe water-soluble anionic macromolecular compound are about 0.05 w/v %and about 1.0 w/v %, respectively.
 29. The method according to claim 27,wherein the concentration of polyvinylpyrrolidone is 0.1-5.0 w/v % andthe water-soluble anionic macromolecular compound is contained at aweight ratio of 0.1-2.0 to the amount of polyvinylpyrrolidone.